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From February 28, 2011 through March 1, 2011, NIMH convened a workshop to discuss recent findings and gaps within the study of sex differences in the brain. It is well established that an individual’s sex can influence susceptibility, prevalence, and age of onset for psychiatric disorders. Despite these clear epidemiological trends, very little is known about the precise timing, neural circuitry, or mechanisms underlying the expression of sex differences in mental disorders.

At this workshop, participants focused on research directed at understanding the mechanisms by which sex differences in affect, cognition, and social behavior arise. Invitees included basic and translational neuroscientists studying animals and humans, with expertise in a variety of methodologies from molecular neuroscience to functional neuroimaging. Primary discussion included how each person’s work could inform the others’, opportunities to develop collaborations, and ideas for how NIMH could optimize progress across the interrelated topics.

The workshop was organized into three sessions, each concerning a different domain of function. Discussants considered each of these topics in light of developmental trajectories. Each session included an introduction by the session moderator, presentations in key areas, and group discussions facilitated by the session moderator.

Topic 1: Cognition

The first session highlighted research in the domain of cognition. Two presentations discussed sex differences in normal human neurodevelopment, with a focus on the structure and function of prefrontal cortex. These demonstrated that maturational thinning of frontal cortex peaks earlier in girls than in boys, and that sex interacts with allelic variability in the catechol-O-methyl transferase (COMT) gene to predict the impact of stress on executive functions. The third presentation focused on individuals with schizophrenia, and on how sex steroid activity affects a range of cognitive tasks. The final two presentations focused on interactions between sex, stress, and learning and memory. These included studies showing sex-specific hemispheric lateralization of amygdala activation in men and women and how acute stress during the perinatal period affected brain organization in a rodent model.

Discussion topics included: (i) the paucity of research examining sex differences at a neurobiological and mechanistic level; (ii) the pervasiveness of sex differences in the brain, when looked for; and, (iii) the need for more neuroscientists to incorporate sex as a variable in experimental designs. Participants also emphasized the need to educate the wider neuroscience community regarding differences between the effects of steroid hormones on brain organization and activity, especially when considering developmental trajectories. Participants also offered ideas for fruitful areas of research, such as including wild-type mice in model animal experiments, focusing on sexual dimorphisms related to stress reactivity, and examining epigenetic changes.

Topic 2: Affect

The second session highlighted research in the domain of affect, with a focus on amygdalo-cortical circuitry in both animals and humans. The first presentation highlighted sex-by-hemisphere effects of amygdala and ventromedial prefrontal cortex lesions on emotion regulation. The second presentation demonstrated that the effects of estradiol on fear extinction are sexually dimorphic. Two presentations focused on organizationally based sexual dimorphisms in the stress system, including findings at the molecular-cellular level. Different levels of corticotrophin-releasing factor (CRF) receptor coupling, signaling, and trafficking can lead to greater sensitivity and decreased adaptability to stress in females. In addition, prenatal stress can disrupt gene de-methylation and microRNA function. The final presentation highlighted the importance of sexually dimorphic brain cell growth and development in hippocampus and the development of glial cells in amygdala.

Discussion topics included the differential vulnerability of males versus females to psychiatric disorders at different stages in development, with males being more at risk during fetal development and childhood, and females being more at risk in puberty and old age. Therefore, the identification of sensitive developmental periods for sexually dimorphic changes in brain structure or function was seen as a critical need. In addition to temporal specificity, discussants noted the regional specificity of findings presented. Identified challenges in the field included the difficulties inherent in modeling emotions in animals, the need for better paradigms to study behavioral sex differences, and the difficulty measuring sex differences with current electrophysiological techniques. Participants thought there were great opportunities to increase collaborations, to engage scientists within the molecular neuroscience community, and to increase education/training in this area.

Topic 3: Social Behavior

The third session highlighted research in the domain of social behavior. The first presentation discussed the trajectory of brain structure in normal human development, with a focus on the importance of temporal and regional specificity of effects. Two presentations examined social behavior in rodents, including social cognition, social proficiency, and juvenile play behaviors. Both sets of data emphasized the ways in which these behaviors can be modulated by hormone independent as well as hormone dependent mechanisms. The last two presentations moved from the systems level to the genetic/genomic level. Presenters highlighted sex-specific gene associations in psychiatric disorders such as autism and the importance of including sex as a factor when examining genomic data. In addition, the potential impact of genomic imprinting was explored. The data presented showed how parent of origin effects are regionally and developmentally specific. Paternal imprinting has a stronger influence in the adult brain; maternal imprinting guides embryonic development.

Discussion topics included the existing framework for how to study sex differences, the utility of the four-core genotype model for separating sex chromosome from hormonal activation effects, and the need to apply these tools systematically to the study of a wider range of phenotypes. Discussants also emphasized the importance of focusing on developmental trajectories, noting that sex differences in the brain may vary considerably by developmental period. Challenges in studying sex differences in social behavior include the ways in which salient stimuli themselves may differ for males and females and the critical importance of species selection. Discussants debated the pros and cons of a top-down approach (from sexually dimorphic clinical disorder to neurobiological mechanism) or a bottom-up approach (from sexually dimorphic biology to behavior), but agreed that it was important to focus on those circuits and domains of most relevance to mental health.